US8754068B2 - Modified C-3 betulinic acid derivatives as HIV maturation inhibitors - Google Patents

Modified C-3 betulinic acid derivatives as HIV maturation inhibitors Download PDF

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Publication number
US8754068B2
US8754068B2 US13/151,706 US201113151706A US8754068B2 US 8754068 B2 US8754068 B2 US 8754068B2 US 201113151706 A US201113151706 A US 201113151706A US 8754068 B2 US8754068 B2 US 8754068B2
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compound
group
coor
cyclopenta
pentamethyl
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US13/151,706
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US20120142707A1 (en
Inventor
Alicia Regueiro-Ren
Jacob Swidorski
Zheng Liu
Nicholas A. Meanwell
Sing-Yuen Sit
Jie Chen
Ny Sin
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ViiV Healthcare UK No 5 Ltd
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Bristol Myers Squibb Co
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Assigned to BRISTOL-MYERS SQUIBB COMPANY reassignment BRISTOL-MYERS SQUIBB COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, JIE, MEANWELL, NICHOLAS A., SIT, SING-YUEN, SWIDORSKI, JACOB, LIU, ZHENG, REGUEIRO-REN, ALICIA
Publication of US20120142707A1 publication Critical patent/US20120142707A1/en
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Assigned to VIIV HEALTHCARE (NO. 5) LIMITED reassignment VIIV HEALTHCARE (NO. 5) LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRISTOL-MYERS SQUIBB COMPANY
Assigned to VIIV HEALTHCARE UK (NO. 5) LIMITED reassignment VIIV HEALTHCARE UK (NO. 5) LIMITED CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY DATA PREVIOUSLY RECORDED ON REEL 039377 FRAME 0129. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: BRISTOL-MYERS SQUIBB COMPANY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • One embodiment of the present invention is directed to a compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:
  • R 1 is isopropenyl or isopropyl; J and E are —H or —CH 3 ; E is absent when the double bond is present;
  • X is a phenyl or heteroaryl ring substituted with A, wherein A is at least one member selected from the group of —H, -halo, -hydroxyl, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkyl, —NR 2 R 2 , —COOR 2 , —C(O)NR 2 R 2 , —C(O)NR 2 SO 2 R 3 , —SO 2 NR 2 R 2 , —NR 2 SO 2 R 2 , —SO 2 NR 2 R 2 , —C 1-6 cycloalkyl-COOR 2 , —C 1-6 alkenyl-COOR 2 , —C 1-6 alkynyl-COOR 2 , —C 1-6 alkyl-COOR 2 ,
  • the compounds of the disclosure herein set forth may be used in combination with HIV entry inhibitors.
  • HIV entry inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194 and Inhibitors of the entry of HIV into host cells . Meanwell, Nicholas A.; Kadow, John F. Current Opinion in Drug Discovery & Development (2003), 6(4), 451-461.
  • the compounds can be utilized in combination with attachment inhibitors, fusion inhibitors, and chemokine receptor antagonists aimed at either the CCR5 or CXCR4 coreceptor.
  • HIV attachment inhibitors are also set forth in U.S. Pat. No. 7,354,924 and US 2005/0209246.
  • the mixture was diluted with 1,4-Dioxane (2 mL) and was flushed with N 2 .
  • the vial was sealed and heated to 85° C. for 15.5 h.
  • the mixture was cooled to rt, was diluted with water (4 mL) and was extracted with dichloromethane (3 ⁇ 4 mL).
  • the combined organic layers were dried with Na 2 SO 4 .
  • the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure.
  • the residue purified by Biotage flash chromatography using a 0-25% EtOAc in hexanes gradient.
  • HIV cell culture assay MT-2 cells and 293T cells were obtained from the NIH AIDS Research and Reference Reagent Program.
  • MT-2 cells were propagated in RPMI 1640 media supplemented with 10% heat inactivated fetal bovine serum, 100 ⁇ g/ml penicillin G and up to 100 units/ml streptomycin.
  • the 293T cells were propagated in DMEM media supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 units/ml penicillin G and 100 ⁇ g/ml streptomycin.
  • FBS heat inactivated fetal bovine serum
  • the proviral DNA clone of NL 4-3 was obtained from the NIH AIDS Research and Reference Reagent Program.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US13/151,706 2010-06-04 2011-06-02 Modified C-3 betulinic acid derivatives as HIV maturation inhibitors Expired - Fee Related US8754068B2 (en)

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US35133810P 2010-06-04 2010-06-04
US13/151,706 US8754068B2 (en) 2010-06-04 2011-06-02 Modified C-3 betulinic acid derivatives as HIV maturation inhibitors

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US20120142707A1 US20120142707A1 (en) 2012-06-07
US8754068B2 true US8754068B2 (en) 2014-06-17

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EP (1) EP2576585B8 (pt)
JP (1) JP5752789B2 (pt)
CN (1) CN103038245B (pt)
AR (1) AR081637A1 (pt)
BR (1) BR112012030818A2 (pt)
CA (1) CA2801487C (pt)
EA (1) EA022393B1 (pt)
ES (1) ES2612452T3 (pt)
MX (1) MX2012013703A (pt)
TW (1) TW201201793A (pt)
WO (1) WO2011153315A1 (pt)

Cited By (9)

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US8889854B2 (en) 2012-05-07 2014-11-18 Bristol-Myers Squibb Company C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity
US8906889B2 (en) 2012-02-15 2014-12-09 Bristol-Myers Squibb Company C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity
WO2015157483A1 (en) 2014-04-11 2015-10-15 Bristol-Myers Squibb Company Triterpenoids with hiv maturation inhibitory activity, substituted in position 3 by a non-aromatic ring carrying a haloalkyl substituent
WO2015195776A1 (en) 2014-06-19 2015-12-23 Bristol-Myers Squibb Company Betulinic acid derivatives with hiv maturation inhibitory activity
US9249180B2 (en) 2013-02-25 2016-02-02 Bristol-Myers Squibb Company C-3 alkyl and alkenyl modified betulinic acid derivatives
WO2016077569A1 (en) 2014-11-14 2016-05-19 Bristol-Myers Squibb Company C17-aryl substituted betulinic acid analogs
WO2016077561A1 (en) 2014-11-14 2016-05-19 Bristol-Myers Squibb Company Oxolupene derivatives
WO2017134596A1 (en) 2016-02-04 2017-08-10 VIIV Healthcare UK (No.5) Limited C-3 and c-17 modified triterpenoids as hiv-1 inhibitors
US20190135857A1 (en) * 2016-06-30 2019-05-09 Viiv Healthcare Uk (No. 5) Limited Triterpenoid inhibitors of human immunodeficiency virus replication

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CA2826113C (en) * 2011-01-31 2018-09-04 Bristol-Myers Squibb Company C-17 and c-3 modified triterpenoids with hiv maturation inhibitory activity
RS54352B1 (en) * 2011-01-31 2016-02-29 Bristol-Myers Squibb Company C-28 AMINES OF C-3 MODIFIED BETULINIC ACID DERIVATIVES AS HIV INVESTIGATION INHIBITORS
CN106822153B (zh) 2011-06-06 2019-12-17 爱荷华大学研究基金会 用于抑制肌萎缩的方法
KR20140069167A (ko) 2011-09-21 2014-06-09 브리스톨-마이어스 스큅 컴퍼니 항바이러스 활성을 갖는 신규 베툴린산 유도체
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
EP2953960A1 (en) * 2013-02-06 2015-12-16 Bristol-Myers Squibb Company C-19 modified triterpenoids with hiv maturation inhibitory activity
US20170129916A1 (en) 2014-06-26 2017-05-11 Hetero Research Foundation Novel betulinic proline imidazole derivatives as hiv inhibitors
AU2015346314B2 (en) * 2014-11-14 2018-04-12 VIIV Healthcare UK (No.5) Limited Extended betulinic acid analogs
MA40886B1 (fr) 2015-02-09 2020-03-31 Hetero Research Foundation Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-28 en tant qu'inhibiteurs du vih
WO2016147099A2 (en) 2015-03-16 2016-09-22 Hetero Research Foundation C-3 novel triterpenone with c-28 amide derivatives as hiv inhibitors
KR20180028534A (ko) 2015-07-28 2018-03-16 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 Hiv 감염을 예방하거나 치료하기 위한 베투인 유도체
CN108026139A (zh) 2015-07-28 2018-05-11 葛兰素史克知识产权第二有限公司 用于预防或治疗hiv感染的白桦脂醇衍生物
KR20180054826A (ko) 2015-09-24 2018-05-24 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 Hiv 성숙 억제 활성을 갖는 화합물
EP3405474A1 (en) 2016-01-20 2018-11-28 Glaxosmithkline Intellectual Property (No. 2) Limited Amine derivatives of lupanes with hiv maturation inhibitory activity
US10493070B2 (en) 2016-06-30 2019-12-03 Viiv Healthcare Uk (No. 5) Limited Azadecalin derivatives as inhibitors of human immunodeficiency virus replication
JP2019519571A (ja) 2016-06-30 2019-07-11 ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド ヒト免疫不全ウイルス複製のアザ置換阻害剤
EP4321164A3 (en) 2018-04-24 2024-04-17 ViiV Healthcare UK (No.5) Limited Compounds with hiv maturation inhibitory activity
PL237998B1 (pl) 2018-05-28 2021-06-28 Narodowy Inst Lekow Fosfonowe pochodne kwasu 3-karboksyacylobetulinowego, sposób ich otrzymywania oraz ich zastosowanie

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Cited By (15)

* Cited by examiner, † Cited by third party
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US8906889B2 (en) 2012-02-15 2014-12-09 Bristol-Myers Squibb Company C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity
US8889854B2 (en) 2012-05-07 2014-11-18 Bristol-Myers Squibb Company C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity
US9249180B2 (en) 2013-02-25 2016-02-02 Bristol-Myers Squibb Company C-3 alkyl and alkenyl modified betulinic acid derivatives
US10245275B2 (en) 2014-04-11 2019-04-02 Viiv Healthcare Uk (No. 4) Limited Triterpenoids with HIV maturation inhibitory activity
WO2015157483A1 (en) 2014-04-11 2015-10-15 Bristol-Myers Squibb Company Triterpenoids with hiv maturation inhibitory activity, substituted in position 3 by a non-aromatic ring carrying a haloalkyl substituent
US11464790B2 (en) 2014-04-11 2022-10-11 ViiV Healthcare UK (No.4) Limited Triterpenoids with HIV maturation inhibitory activity
EP3750910A1 (en) 2014-04-11 2020-12-16 VIIV Healthcare UK(No.4) Limited Triterpenoids with hiv maturation inhibitory activity
US9527882B2 (en) 2014-04-11 2016-12-27 ViiV Healthcare UK (No.4) Limited Triterpenoids with HIV maturation inhibitory activity
US10780102B2 (en) 2014-04-11 2020-09-22 Viiv Healthcare Uk (No. 4) Limited Triterpenoids with HIV maturation inhibitory activity
WO2015195776A1 (en) 2014-06-19 2015-12-23 Bristol-Myers Squibb Company Betulinic acid derivatives with hiv maturation inhibitory activity
WO2016077561A1 (en) 2014-11-14 2016-05-19 Bristol-Myers Squibb Company Oxolupene derivatives
WO2016077569A1 (en) 2014-11-14 2016-05-19 Bristol-Myers Squibb Company C17-aryl substituted betulinic acid analogs
WO2017134596A1 (en) 2016-02-04 2017-08-10 VIIV Healthcare UK (No.5) Limited C-3 and c-17 modified triterpenoids as hiv-1 inhibitors
EP3831839A2 (en) 2016-02-04 2021-06-09 ViiV Healthcare UK (No.5) Limited C-3 and c-17 modified triterpenoids as hiv-1 inhibitors
US20190135857A1 (en) * 2016-06-30 2019-05-09 Viiv Healthcare Uk (No. 5) Limited Triterpenoid inhibitors of human immunodeficiency virus replication

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EA022393B1 (ru) 2015-12-30
AR081637A1 (es) 2012-10-10
BR112012030818A2 (pt) 2019-09-24
US20120142707A1 (en) 2012-06-07
TW201201793A (en) 2012-01-16
CA2801487A1 (en) 2011-12-08
EP2576585B1 (en) 2016-10-12
JP2013527242A (ja) 2013-06-27
CA2801487C (en) 2017-12-05
EA201270780A1 (ru) 2013-04-30
CN103038245B (zh) 2015-03-25
WO2011153315A1 (en) 2011-12-08
MX2012013703A (es) 2012-12-17
JP5752789B2 (ja) 2015-07-22
ES2612452T3 (es) 2017-05-17
EP2576585A1 (en) 2013-04-10
CN103038245A (zh) 2013-04-10
EP2576585B8 (en) 2016-12-21

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